Despite enormous investments of financial and human resources, cancer remains one of the major causes of death. For example, cancer is the leading cause of death in women between the ages of 35 and 74. Standard approaches to treat cancer have centered around a combination of surgery, radiation and chemotherapy. Alternative approaches are needed not only to treat cancer, but also to prevent cancer.
A new generation of tumor antigens has been defined: “self proteins” (J. Exp. Med. 180:1-4, 1994; Cell 82:13-17, 1995). Self tumor antigens are proteins that are expressed by both normal cells and cancer cells. (As opposed to mutated proteins that are unique and thus cancer specific.) Self tumor antigens are typically overexpressed by the cancer cells. Certain self proteins, such as HER-2/neu and c-myc, are known to be involved in malignant transformation.
A common characteristic of malignancies is uncontrolled cell growth. Cancer cells appear to have undergone a process of transformation from the normal phenotype to a malignant phenotype capable of autonomous growth. Amplification and overexpression of somatic cell genes is considered to be a common primary event that results in the transformation of normal cells to malignant cells. The malignant phenotypic characteristics encoded by the oncogenic genes (oncogenes) are passed on during cell division to the progreny of the transformed cells.
Certain proto-oncogenes appear to be activated to a cellular oncogene through quantitative mechanisms that result from increased or deregulated expression (overexpression) of an essentially normal gene product. For example, the myc gene family has been associated with initiation and/or progression of certain human lymphomas and carcinomas, whose transforming activation is the result of quantitative mechanisms. Proto-oncogenes are believed to be essential for certain aspects of normal cellular physiology. In this regard, the HER-2/neu oncogene is a member of the tyrosine protein kinase family of oncogenes and shares a high degree of homology with the epidermal growth factor receptor. HER-2/neu presumably plays a role in cell growth and/or differentiation. HER-2/neu appears to induce malignancies through quantitative mechanisms that result from increased or deregulated expression of an essentially normal gene product.
HER-2/neu (p185) is the protein product of the HER-2/neu oncogene. The HER-2/neu gene is amplified and the HER-2/neu protein is overexpressed in a variety of cancers including breast, ovarian, colon, lung and prostate cancer. HER-2/neu is related to malignant transformation. It is found in 50%-60% of ductal in situ carcinoma and 20%-40% of all breast cancers, as well as a substantial fraction of adenocarcinomas arising in the ovaries, prostate, colon and lung. HER-2/neu is intimately associated not only with the malignant phenotype, but also with the aggressiveness of the malignancy, being found in one-fourth of all invasive breast cancers. HER-2/neu overexpression is correlated with a poor prognosis in both breast and ovarian cancer. HER-2/neu is a transmembrane protein with a relative molecular mass of 185 kd that is approximately 1255 amino acids (aa) in length. It has an extracellular binding domain (ECD) of approximately 645 aa, with 40% homology to epidermal growth factor receptor (EGFR), a highly hydrophobic transmembrane anchor domain (TMD), and a carboxyterminal intracellular domain (ICD) of approximately 580 aa with 80% homology to EGFR.
Thus, HER-2/neu and c-myc, which are normal proteins found to be associated with malignant transformation when overexpressed, are examples of self tumor antigens. Other examples of self tumor proteins are those expressed by melanoma cells as melanocyte differentiation antigens, such as gp100, MAGE and MART-1. Self tumor proteins have been found to stimulate an immune response in some patients whose cancers express those proteins (e.g., J. Exp. Med. 179:921-930, 1994; 179:1005-1009, 1994; and 180:347-352, 1994). However, despite the presence of a detectable immune response to self tumor antigens in some patients, immunologic tolerance exists and represents a potential barrier to effectively vaccinating against tumor antigens. For example, rats vaccinated with either purified rat neu protein or rat neu extracellular domain (ECD) expressed by vaccinia virus do not develop rat neu specific immunity (Proc. Natl. Acad. Sci. USA 84:6854-6858, 1987). Tolerance can be circumvented in the rat, however, by immunization with peptides derived from the rat neu protein sequence. Nevertheless, the use of peptides may be problematic as they are thought of as weak immunogens and HLA restriction may limit usefulness (e.g., by preventing the use of a single peptide for all patients). An ideal vaccine strategy targeting a self tumor antigen would be one in which vigorous immunity could be elicited with one vaccine formulation for all patients.
Due to the difficulties in the current approaches to treatment and prevention of cancer, there is a need in the art for improved methods and compositions. The present invention fulfills this need, and further provides other related advantages.